Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity.

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit that acts as a gatekeeper of cocaine-induced behavioral plasticity. However, the molecular and circuit mechanisms underlying this function are unknown. Here, we show that GPe parvalbumin-positive (GPePV) cells mediate cocaine responses by selectively modulating ventral tegmental area dopamine (VTADA) cells projecting to the dorsomedial striatum (DMS). Interestingly, GPePV cell activity in cocaine-naive mice is correlated with behavioral responses following cocaine, effectively predicting cocaine sensitivity. Expression of the voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability following cocaine was downregulated, contributing to the elevation in GPePV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPePV cell excitability and impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its therapeutic potential to counteract psychostimulant use disorder.

Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity.

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit, receiving strong input from the indirect pathway and regulating a variety of functions, including locomotor output and habit formation. We recently showed that it also acts as a gatekeeper of cocaine-induced behavioral plasticity, as inhibition of parvalbumin-positive cells in the GPe (GPe PV ) prevents the development of cocaine-induced reward and sensitization. However, the molecular and circuit mechanisms underlying this function are unknown. Here we show that GPe PV cells control cocaine reward and sensitization by inhibiting GABAergic neurons in the substantia nigra pars reticulata (SNr GABA ), and ultimately, selectively modulating the activity of ventral tegmental area dopamine (VTA DA ) cells projecting to the lateral shell of the nucleus accumbens (NAcLat). A major input to GPe PV cells is the indirect pathway of the dorsomedial striatum (DMS D 2 ), which receives DAergic innervation from collaterals of VTA DA →NAcLat cells, making this a closed-loop circuit. Cocaine likely facilitates reward and sensitization not directly through actions in the GPe, but rather in the upstream DMS, where the cocaine-induced elevation of DA triggers a depression in DMS D 2 cell activity. This cocaine-induced elevation in DA levels can be blocked by inhibition of GPe PV cells, closing the loop. Interestingly, the level of GPe PV cell activity prior to cocaine administration is correlated with the extent of reward and sensitization that animals experience in response to future administration of cocaine, indicating that GPe PV cell activity is a key predictor of future behavioral responses to cocaine. Single nucleus RNA-sequencing of GPe cells indicated that genes encoding voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability are downregulated in GPe PV cells following a single cocaine exposure, contributing to the elevation in GPe PV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPe PV cell excitability and also impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its potential as a therapeutic to counteract psychostimulant use disorder. Our findings illuminate the molecular and circuit mechanisms by which the GPe orchestrates brain-wide changes in response to cocaine that are required for reward, sensitization, and self-administration behaviors.

Neural circuit basis of adolescent THC-induced potentiation of opioid responses in adult mice.

Use of one drug of abuse typically influences the behavioral response to other drugs, either administered at the same time or a subsequent time point. The nature of the drugs being used, as well as the timing and dosing, also influence how these drugs interact. Here, we tested the effects of adolescent THC exposure on the development of morphine-induced behavioral adaptations following repeated morphine exposure during adulthood. We found that adolescent THC administration impacted morphine-induced behaviors across several dimensions, including potentiating reward and paradoxically impairing the development of morphine reward. We then mapped the whole-brain response to a reinstatement dose of morphine, finding that adolescent THC administration led to increased activity in the basal ganglia and increased functional connectivity between frontal cortical regions and the ventral tegmental area. Last, we show using rabies virus-based circuit mapping that adolescent THC exposure triggers a long-lasting elevation in connectivity from the frontal cortex regions onto ventral tegmental dopamine cells that has the potential to influence dopaminergic response to morphine administration during adulthood. Our study adds to the rich literature on the interaction between drugs of abuse and provides potential circuit substates by which adolescent THC exposure influences responses to morphine later in life.

Analysis of changes in inter-cellular communications during Alzheimer's Disease pathogenesis reveals conserved changes in glutamatergic transmission in mice and humans.

Analysis of system-wide cellular communication changes in Alzheimer's disease (AD) has recently been enabled by single nucleus RNA sequencing (snRNA-seq) and new computational methods. Here, we combined these to analyze data from postmortem human tissue from the entorhinal cortex of AD patients and compared our findings to those from multiomic data from the 5xFAD amyloidogenic mouse model at two different time points. Using the cellular communication inference tool CellChat we found that disease-related changes were largely related to neuronal excitability as well as synaptic communication, with specific signaling pathways including BMP, EGF, and EPHA, and relatively poor conservation of glial-related changes during disease. Further analysis using the neuron-specific NeuronChat revealed changes relating to metabotropic glutamate receptors as well as neuronal adhesion molecules including neurexins and neuroligins. Our results that cellular processes relating to excitotoxicity are the best conserved between 5xFAD mice and AD suggest that excitotoxicity is the main common feature between pathogenesis in 5xFAD mice and AD patients.

An extended amygdala-midbrain circuit controlling cocaine withdrawal-induced anxiety and reinstatement.

Although midbrain dopamine (DA) circuits are central to motivated behaviors, our knowledge of how experience modifies these circuits to facilitate subsequent behavioral adaptations is limited. Here we demonstrate the selective role of a ventral tegmental area DA projection to the amygdala (VTADA→amygdala) for cocaine-induced anxiety but not cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach reveals a persistent elevation in spontaneous and task-related activity of inhibitory GABAergic cells from the bed nucleus of the stria terminalis (BNST) and downstream VTADA→amygdala cells that can be detected even after a single cocaine exposure. Activity in BNSTGABA→midbrain cells is related to cocaine-induced anxiety but not reward or sensitization, and silencing this projection prevents development of anxiety during protracted withdrawal after cocaine administration. Finally, we observe that VTADA→amygdala cells are strongly activated after a challenge exposure to cocaine and that activity in these cells is necessary and sufficient for reinstatement of cocaine place preference.

A connectomic analysis of deep brain stimulation for treatment-resistant depression.

OBJECTIVE: Deep brain stimulation (DBS) has been used as a treatment of last resort for treatment-resistant depression (TRD) for more than a decade. Many DBS targets have been proposed and tested clinically, but the underlying circuit mechanisms remain unclear. Uncovering white matter tracts (WMT) activated by DBS targets may provide crucial information about the circuit substrates mediating DBS efficacy in ameliorating TRD. METHODS: We performed probabilistic tractography using diffusion magnetic resonance imaging datas from 100 healthy volunteers in Human Connectome Project datasets to analyze the structural connectivity patterns of stimulation targeting currently-used DBS target for TRD. We generated mean and binary fiber distribution maps and calculated the numbers of WMT streamlines in the dataset. RESULTS: Probabilistic tracking results revealed that activation of distinct DBS targets demonstrated modulation of overlapping but considerably distinct pathways. DBS targets were categorized into 4 groups: Cortical, Striatal, Thalamic, and Medial Forebrain Bundle according to their main modulated WMT and brain areas. Our data also revealed that Brodmann area 10 and amygdala are hub structures that are associated with all DBS targets. CONCLUSIONS: Our results together suggest that the distinct mechanism of DBS targets implies individualized target selection and formulation in the future of DBS treatment for TRD. The modulation of Brodmann area 10 and amygdala may be critical for the efficacy of DBS-mediated treatment of TRD.